Skeletal joints provide a movable union of two or more bones. Synovial joints are highly evolved articulating joints that permit free movement. Because mammalian lower limbs are concerned with locomotion and upper limbs provide versatility of movement, most of the joints in the extremities are of the synovial type. There are various types of synovial joints. Their classification is based upon the types of active motion that they permit (uniaxial, biaxial, and polyaxial). They are differentiated further according to their principal morphological features (hinge, pivot, condyloid). In contrast to fibrous and cartilaginous joints where the ends of the bones are found in continuity with intervening tissue, the ends of the bones in a synovial joint are in contact, but separate. Because the bones are not bound internally, the integrity of a synovial joint results from its ligaments and capsule (which bind the articulation externally) and to some extent from the surrounding muscles. In synovial joints, the contiguous bony surfaces are covered with articular or, hyaline cartilage, and the joint cavity is surrounded by a fibrous capsule which segregates the joint from the surrounding vascularized environment. The inner surface of the capsule is lined by a synovial layer or "membrane" containing cells involved in secreting the viscous lubricating synovial fluid. Gray, Anatomy of the Human Body, pp. 312; 333-336 (13th ed.; C. C. Clemente, ed., (1985)).
In certain synovial joints, the joint or synovial cavity may be divided by a meniscus of fibrocartilage. Synovial joints involving two bones and containing a single joint cavity are referred to as simple joints. Joints that contain a meniscus forming two joint cavities are called composite joints. The term compound joint is used for those articulations in which more than a single pair of articulating surfaces are present.
Joint replacement, particularly articulating joint replacement, is a commonly performed procedure in orthopedic surgery. However, the ideal material for replacement joints remains elusive. Typically, joint reconstruction requires repair of the bony detect, the articular cartilage and, in addition, one or more of the joining ligaments. To date, there are no satisfactory clinical means for readily repairing both articular cartilage and bony defects within a joint which reliably results in viable, fully-functional weight-bearing joints. Prosthetic joints which replace all the endogenous joint tissues circumvent some of these problems. However, prosthetic joints have numerous, well documented limitations, particularly in younger and highly active patients. In addition, in some circumstances prosthetic joint replacement is not possible and repair options are limited to osteochondroallograft materials.
The articular, or hyaline cartilage, found at the end of articulating bones is a specialized, histologically distinct tissue and is responsible for the distribution of load resistance to compressive forces, and the smooth gliding that is part of joint function. Articular cartilage has little or no self-regenerative properties. Thus, if the articular cartilage is torn or worn down in thickness or is otherwise damaged as a function of time, disease or trauma, its ability to protect the underlying bone surface is compromised.
Other types of cartilage in skeletal joints include fibrocartilage and elastic cartilage. Secondary cartilaginous joints are formed by discs of fibrocartilage which join vertebrae in the vertebral column. In fibrocartilage, the mucopoly-saccharide network is interlaced with prominent collagen bundles and the chondrocytes are more widely scattered than in hyaline cartilage. Elastic cartilage contains collagen fibers which are histologically similar to elastin fibers. As with other connective tissues the formation of cartilaginous tissue is a complex biological process, involving the interaction of cells and collagen fibers in a unique biochemical milieu.
Cartilage tissue, including articular cartilage, unlike other connective tissues, lacks blood vessels, nerves, lymphatics and basement membrane. Cartilage is composed of chondrocytes which synthesize an abundant extracellular milieu composed of water, collagens, proteoglycans and noncollagenous proteins and lipids. Collagen serves to trap proteoglycans and to provide tensile strength to the tissue. Type II collagen is the predominant collagen in cartilage tissue. The proteoglycans are composed of a variable number of glycosaminoglycan chains, keratin sulphate, chondroitin sulphate and/or dermatan sulphate, and N-linked and O-linked oligosaccharides covalently bound to a protein core. The sulfated glycosaminoglycans are negatively charged resulting in an osmotic swelling pressure that draws in water.
In contrast, certain collagens such as the fibrotic cartilaginous tissues which occur in scar tissue for example, are keloid and typical of scar-type tissue, i.e., composed of capillaries and abundant, irregular, disorganized bundles of Type I and Type II collagen.
Histologically, articular or hyaline cartilage can be distinguished from other forms of cartilage, both by its morphology and by its biochemistry. Morphologically, articular cartilage is characterized by superficial versus mid versus deep "zones" which show a characteristic gradation of features from the surface of the tissue to the base of the tissue adjacent to the bone. In the superficial zone, for example, chondrocytes are flattened and lie parallel to the surface embedded in an extracellular network that contains tangentially arranged collagen and few proteoglycans. In the mid zone, chondrocytes are spherical and surrounded by an extracellular network rich in proteoglycans and obliquely organized collagen fibers. In the deep zone, close to the bone, the collage fibers are vertically oriented. The keratin sulphate rich proteoglycans increase in concentration with increasing distance from the cartilage surface. For a detailed description of articular cartilage micro-structure, see, for example, (Aydelotte and Kuettner, (1988), Conn. Tiss. Res. 18:205; Zanetti et al., (1985), J. Cell Biol. 101:53; and Poole et al., (1984), J. Anat. 138:13.
Biochemically, articular collagen can be identified by the presence of Type II and Type IX collagen, as well as by the presence of well-characterized proteoglycans, and by the absence of Type X collagen, which is associated with endochondral bone formation.
In normal articular cartilage, a balance exists between synthesis and destruction of the above-described extracellular network. However, in tissue subjected to repeated trauma, for example due to friction between misaligned bones in contact with one another, or in joint diseases characterized by net loss of articular cartilage, e.g., osteoarthritis, an imbalance occurs between synthesis and degradation.
Two types of defects are recognized in articular surfaces, i.e., full-thickness defects and superficial defects. These defects differ not only in the extent of physical damage to the cartilage, but also in the nature of the repair response each type of lesion can elicit.
Full-thickness defects of an articulating surface include damage to the hyaline cartilage, the calcified cartilage layer and the subchondral bone tissue with its blood vessels and bone marrow. Full-thickness defects can cause severe pain since the bone plate contains sensory nerve endings. Such defects generally arise from severe trauma and.backslash.or during the late stages of degenerative joint disease, such as osteoarthritis. Full-thickness defects may, on occasion, lead to bleeding and the induction of a repair reaction from the subchondral bone. In such instances, however, the repair tissue formed is a vascularized fibrous type of cartilage with insufficient biomechanical properties, and does not persist on a long-term basis.
In contrast, superficial defects in the articular cartilage tissue are restricted to the cartilage tissue itself. Such defects are notorious because they do not heal and show no propensity for repair reactions. Superficial defects may appear as fissures, divots, or clefts in the surface of the cartilage, or they may have a "crab-meat" appearance in the affected tissue. They contain no bleeding vessels (blood spots) such as are seen in full-thickness defects. Superficial defects may have no known cause, however, they are often the result of mechanical derangements which lead to a wearing down of the cartilaginous tissue. Such mechanical derangements may be caused by trauma to the joint, e.g., a displacement of tom meniscus tissue into the joint, meniscectomy, a taxation of the joint by a tom ligament, malalignment of joints, or bone fracture, or by hereditary diseases. Superficial defects are also characteristic of early stages of degenerative joint diseases, such as osteoarthritis. Since the cartilage tissue is not innervated or vascularized, superficial defects do not heal and often degenerate into full-thickness defects.
Replacement with prosthetic joints is currently the preferred option for serious degeneration of joint function involving loss of articular cartilage. It is anticipated that a means for functional reconstruction of joint complexes, including regeneration and repair of articular cartilage, will have a profound effect on alloplastic joint replacement surgery and the management of degenerative joint disease.
Like articular cartilage, joint ligaments which serve to connect interacting bones in the joint, have little or no self-regenerative properties. Ligaments typically are composed of substantially parallel bundles of white fibrous tissue. They are pliant and flexible to allow substantially complete freedom of movement, but are inextensile to prevent over-extension of the interacting bones in the joint. Like cartilage, ligament tissue is substantially devoid of blood vessels and has little or no self-regenerative properties. Surgical repair of torn or damaged ligament tissue to date is limited to use of autogenous grafts or synthetic materials that are surgically attached to the articular extremities of the bones. Allogenic ligaments typically fail mechanically, presumably due to the treatments required to render these materials biocompatible. Similarly, tendons are rope-like structures which connect muscle fibers to bone or cartilage and which are formed from substantially parallel fibroids of white connective tissue. The synovial capsule is composed of a thin layer of ligamentous tissue which encloses the joint and allows the joint to be bathed in the lubricating synovial fluid. The interior of the joint capsule is lined with a thin membrane of connective tissue having branched connective-tissue corpuscles defining the synovial membrane, and which is primarily responsible for secreting synovial fluid into the cavity. The integrity of this membrane therefore, is important to maintaining a source for the lubricating synovial fluid. Repair of these tissues in orthopedic contexts typically is limited to resuturing of existing tissue.
Bone tissue differs significantly from the other tissues described hereinabove, including cartilage tissue. Specifically, bone tissue is vascularized tissue composed both of cells and a biphasic medium which is composed of a mineralized, inorganic component (primarily hydroxyapatite crystals) and an organic component comprised primarily of Type I collagen. Glycosaminoglycans constitute less than 2% of this organic component and less than 1% of the biphasic medium itself or of bone tissue per se. Moreover, relative to cartilage tissue, the collagen present in bone tissue exists in a highly-organized parallel arrangement.
Bony defects, whether from degenerative, traumatic or cancerous etiologies, pose a formidable challenge to the reconstructive surgeon. Particularly difficult is reconstruction or repair of skeletal parts that comprise part of a multi-tissue complex, such as occurs in mammalian joints.
Mammalian bone tissue is known to contain one or more proteinaceous materials presumably active during growth and natural bone healing which can induce a developmental cascade of cellular events resulting in endochondral bone formation. The developmental cascade involved in endochondral bone differentiation consists of chemotaxis of mesenchymal cells, proliferation of progenitor cells into chondrocytes and osteoblasts, differentiation of cartilage, vascular invasion, bone formation, remodeling, and finally marrow differentiation.
True osteogenic factors capable of inducing the above-described cascade of events that result in endochondral bone formation have now been identified, isolated, and cloned. These proteins, which occur in nature as disulfide-bonded dimeric proteins, are referred to in the art as "osteogenic" proteins, "osteoinductive" proteins, and "bone morphogenetic" proteins. Whether naturally-occurring or synthetically prepared, these osteogenic proteins, when implanted in a mammal typically in association with a substrate that allows the attachment, proliferation and differentiation of migratory progenitor cells, are capable of inducing recruitment of accessible progenitor cells and stimulating their proliferation, inducing differentiation into chondrocytes and osteoblasts, and further inducing differentiation of intermediate cartilage, vascularization, bone formation, remodeling, and finally marrow differentiation. Those proteins are referred to as members of the Vgr-1/OP1 protein subfamily of the TGF.beta. super gene family of structurally related proteins. Members include the proteins described in the art as OP1 (BMP-7), OP2 (BMP-8), BMP2, BMP3, BMP4, BMP5, BMP6, 60A, DPP, Vgr-1 and Vgl. See., e.g., U.S. Pat. No. 5,011,691; U.S. Pat. No. 5,266,683, Ozkaynak et al. (1990) EMBO J. 9: 2085-2093, Wharton et al. (1991) PNAS 88:9214-9218), (Ozkaynak (1992) J. Biol. Chem. 267:25220-25227 and U.S. Pat. No. 5,266,683); (Celeste et al. (1991) PNAS 87:9843-9847); (Lyons et al. (1989) PNAS 86:4554-4558). These disclosures describe the amino acid and DNA sequences, as well as the chemical and physical characteristics of these proteins. See also (Wozney et al. (1988) Science 242:1528-1534); BMP 9 (WO93/00432, published Jan. 7, 1993); DPP (Padgett et al. (1987) Nature 325:81-84; and Vg-1 (Weeks (1987) Cell 51:861-867).
It is an object of the instant invention to provide a bioresorbable matrix and device, suitable for regenerating body parts which comprise two or more functionally- and structurally-associated yet distinct replacement tissues in a mammal. Another object is to provide compositions and methods for the repair or complete reconstruction of a mechanically and functionally viable skeletal joint in a mammal, particularly an articulating or synovial joint, as well as other body parts comprising bone and bona fide hyaline cartilage, without relying on prosthetic devices. Another object is to provide materials and methods for the repair of tissue defects in an articulating mammalian joint, so as to form a mechanically and functionally viable joint comprising bone and articular cartilage, ligament, tendon, synovial membrane and synovial capsule tissue. Another object of the invention is to provide means for restoring functional non-mineralized tissue in a skeletal joint including the avascular tissue therein.